Our research to date has demonstrated that cigarette smokers exhibit enhanced basal hypothalamic-pituitary-adrenocortical (HPA) activity and attenuated cortisol responses to multiple stress procedures. Our particularly important finding has been that this altered stress response predicts early smoking relapse. It is well-established that the endogenous opioid system plays a critical role in HPA regulation and that both systems are involved in regulating mood and reinforcing effects of drug use. The extent to which altered HPA response in smokers is due to disrupted endogenous opioid regulation is unknown and is the focus of the proposed research. Preliminary findings on the effects of opioid blockade on HPA stress response indicate that diminished opioid tone may be one potentially important mechanism. The extent to which these opioid-HPA alterations are modified by smoking abstinence and the extent to which they exacerbate symptoms associated with abstinence will be elucidated by this research. We have also demonstrated sex differences with respect to relapse predictors. The proposed research will examine and clarify sex differences in hormonal response patterns during an opioid blockade challenge and in response to stress in dependent female and male smokers. In combination, the findings to date and the potential discovery of an important pathway for stress effects on smoking point to the importance of delineating the opioid-HPA interactions. Confirmation of dysregulated endogenous opioid tone in abstinent smokers and in response to stress will set the stage for refined investigations to develop biobehavioral markers of nicotine dependence, stress-related craving, and relapse. PUBLIC HEALTH RELEVANCE: Tobacco addiction/dependence is the leading preventable cause of cancer and cardiovascular diseases. Stress is widely cited as a reason for continued smoking and for relapse in those attempting to achieve long term abstinence. The proposed research extends our program to identify biobehavioral mechanisms and determinants of stress effects on smoking. This will set the stage for research to determine relapse vulnerability markers. In turn, this will provide unique opportunities for prediction and development of targeted interventions.